Project Summary: 1-in-3 persons with type 2 diabetes (T2DM) develop chronic kidney disease (CKD), which is characterized by progressive renal dysfunction leading to end-stage renal disease. TGF-beta, a protein stimulated in response to elevated blood glucose and systemic inflammation of diabetes, causes fibrotic- thickening of the glomerular basement membrane and damages the structural supports (podocytes) of the kidney's filtration barrier - resulting in impaired renal filtration. The metabolic sequelea of T2DM and CKD also, synergistically, alter skeletal muscle's ubiquitin-proteasome and autophagy-lysosome pathways (degradative pathways), satellite cell function (muscle reparative cells), and mitochondrial health (muscle energetic machinery) -- resulting in muscle breakdown, intermuscular adipose/fibrotic tissue (IMAT) accrual, exercise intolerance, and immobility that exacerbates CKD. The temporal nature of these changes in CKD, however, remains unknown. With mandates from the Center for Disease Control (CDC) urging avenues of treatment that impede the progression of CKD, it is critical now, more than ever, to gain a better understanding of the factors that contribute to disease progression. This will inform more effective targeted interventions. We therefore aim to determine how common metabolic changes in T2DM promote renal fibrosis and renal dysfunction, and in-turn, how renal dysfunction dictates the activity of muscle degredative pathways, the status of muscle reparative cells, and the energetic production of muscle. We will also determine the relationship between these muscle pathways and muscle quality, performance and physical mobility. This will be determined across stages of CKD. Muscle pathway analysis will be analyzed via immunoblotting of muscle tissue samples for relative concentrations of key proteins that govern these pathways, while the status of muscle reparative cells will be determined by their expression of specific regulatory genes and their capacity to form mature muscle in an isolated environment. Muscle energetic production will be assessed by Polarographic respiration tracking of muscle mitochondrial oxidative function (via muscle biopsy). Muscle quality will be assessed with MRI. Renal filtration will be estimated via serum concentrations of cystatin C protein, and fibrotic damage assessed via urinary concentrations of pro-fibrotic protein (TGF-beta) and a constituent of the protein support structures of the kidney (Podocalyxin). Muscle performance will be assessed with an isokinetic dynamometer, with physical mobility evaluated with a functional performance test battery. A cross-sectional research design (15 in each CKD stage; 1/2, 3, and 4/5, total N=45) will be used to examine the relationship between stage of CKD and the specific activity of physiological contributors to muscular decline and how these pathways, in turn, relate to muscle volume, performance, and quality. This research may advance the understanding of when, how, and what form of exercise may impede/reverse CKD progression in those most at risk ? those with diabetes.